The field of salivary gland biology and regeneration is severely hampered by a lack of knowledge regarding the identification of stem or progenitor cells and the fate of this population following salivary gland damage. The cell label retaining approach can objectively identify long living and non-proliferative cells that are hypothesized to be stem and/or progenitor cells. This proposal will utilize the label retaining cell (LRC) techniqu within two established models of salivary gland restoration, post-radiation injections of insulin-like growth factor (IGF1) [3] and ductal ligation/deligation [4], in order to create a more universl understanding of salivary gland regeneration following injury. The central hypothesis of this proposal is label retaining cells play an important role in orchestrating salivary gland regeneration through reestablishment of apical- basal polarity. Specific Aim 1 will demonstrate the regenerative potential of salivary BrdU label retaining cells (LRC). Specific Aim 2 will evaluate the intrinsic role of apical-basal polarity within label retaining cells in restoration of cellular differentiation. Specific Aim 3 will determine the non-cell autonomous effect of loss of polarity on the compensatory proliferation response of label retaining cells. The general goal of this proposal is to identify the capacity of label retaining cells to regenerate differentiated salivary gland structures, and to identify the role of polarity signaling mechanism in promoting differentiation and functional reconstitution. The long-term goal of this proposal is to evaluate whether novel therapies that promote apical-basal polarity within salivary stem/progenitor cells and their respective niches could improve clinical therapeutics for chronic salivary gland dysfunction and xerostomia following radiation therapy for head and neck cancer.